Bortezomib Restores Defective Apoptosis by Upregulation of Noxa in Enteropathy-Associated T-Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2722-2722
Author(s):  
Laura R de Baaij ◽  
Marijn Radersma ◽  
Jolanda MW van de Water ◽  
Kim BJ Groot ◽  
Nathalie J Hijmering ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Tumor Cells ◽  
Cell Lymphoma ◽  
Chemotherapy Resistance ◽  
Intraepithelial Lymphocytes ◽  
T Cell Lymphoma ◽  
Caspase 9 ◽  
Apoptosis Pathway ◽  
Induction Of Apoptosis

Abstract Abstract 2722 Enteropathy-associated T-cell lymphoma (EATL) is a rare intestinal lymphoma that arises from intraepithelial lymphocytes. Clinical outcome of patients with EATL is very poor, due to chemotherapy-resistance and high relapse rates. Therefore, new therapeutic options for EATL are urgently needed. Studies in other types of lymphoma have shown that inhibition of apoptosis may cause chemotherapy-resistance and that restoration of defective apoptosis can induce cell death in these lymphomas. Preliminary data in EATL samples have demonstrated an increased expression of a fraction of NF-κB target genes, suggesting upregulation of NF-κB activity in EATL tumor cells. NF-κB activity can be inhibited by the proteasome inhibitor bortezomib resulting in induction of apoptosis. In the present study, we evaluated if apoptosis is inhibited in EATL cells and if Bortezomib can restore apoptosis in EATL cells. Laser-capture microdissection was applied to 16 fresh frozen EATL samples to obtain purified tumor cells for RNA isolation. Intraepithelial lymphocytes (IEL) of healthy controls were obtained from fresh duodenal biopsies and isolated by cell sorting. RT-MLPA analysis revealed that the pro-apoptotic BH3-only gene Noxa was significantly downregulated in most EATL samples compared to healthy donor IEL. Induction with etoposide resulted in caspase-9 mediated apoptosis in EATL cells with relatively high Noxa expression, whereas in EATL cells with low Noxa expression no apoptosis was induced, suggesting an inhibition in the intrinsic apoptosis pathway. Treatment with Bortezomib resulted in induction of apoptosis in EATL cells. The lethal dose (LD50) varied between 7.5 nM and 15 nM. Bortezomib induced cell death in EATL cells was caspase-9 mediated. mRNA and protein expression analysis showed upregulation of Noxa after incubation with bortezomib. In conclusion, our study showed that bortezomib induces apoptosis by upregulation of Noxa in EATL cells. Bortezomib therefore may be a potential drug in the treatment of patients with EATL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Immune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma

2020 ◽  
Author(s):  
Darci Phillips ◽  
Magdalena Matusiak ◽  
Belén Rivero Gutierrez ◽  
Salil S. Bhate ◽  
Graham L. Barlow ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Response ◽  
Tumor Cells ◽  
Spatial Organization ◽  
Cell Lymphoma ◽  
Post Treatment ◽  
T Cell Lymphoma ◽  
T Cell Subsets ◽  
Cutaneous T Cell Lymphoma

Anti-PD-1 immunotherapies have transformed cancer treatment, yet the determinants of clinical response are largely unknown. We performed CODEX multiplexed tissue imaging and RNA sequencing on 70 tumor regions from 14 advanced cutaneous T cell lymphoma (CTCL) patients enrolled in a clinical trial of pembrolizumab therapy. Clinical response was not associated with the frequency of tumor-infiltrating T cell subsets, but rather with striking differences in the spatial organization and functional immune state of the tumor microenvironment (TME). After treatment, pembrolizumab responders had a localized enrichment of tumor and CD4+ T cells, which coincided with immune activation and cytotoxic PD-1+ CD4+ T cells. In contrast, non-responders had a localized enrichment of Tregs pre- and post-treatment, consistent with a persistently immunosuppressed TME and exhausted PD-1+ CD4+ T cells. Integrating these findings by computing the physical distances between PD-1+ CD4+ T cells, tumor cells, and Tregs revealed a spatial biomarker predictive of pembrolizumab response. Finally, the chemokine CXCL13 was upregulated in tumor cells in responders post-treatment, suggesting that chemoattraction of PD-1+ CD4+ T cells towards tumor cells facilitates a positive outcome. Together, these data show that T cell topography reflects the balance of effector and suppressive activity within the TME and predicts clinical response to PD-1 blockade in CTCL.

Programmed Cell Death 1 and Programmed Cell Death Ligands in Extranodal Natural Killer/T Cell Lymphoma: Expression Pattern and Potential Prognostic Relevance

2019 ◽  
Vol 143 (1) ◽  
pp. 78-88 ◽  
Author(s):  
Hamidah Muhamad ◽  
Narittee Suksawai ◽  
Thamatorn Assanasen ◽  
Chantana Polprasert ◽  
Udomsak Bunworasate ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
Natural Killer ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Lymphoma Cells ◽  
Natural Killer T Cell ◽  
Programmed Cell Death 1 ◽  
Killer T Cell

The programmed cell death 1/programmed cell death ligands (PD-1/PD-Ls) axis is a potential immune escape mechanism of cancers. However, data on the PD-1/PD-Ls pathway in EBV-associated extranodal natural killer/T cell lymphoma (ENKTL) and its clinical implication are limited. Herein, we characterized PD-1/PD-L expression and its prognosis relevance in 49 ENKTL patients in Thailand. PD-L1 was expressed frequently on both lymphoma cells (61.2%) and stroma (77.5%), whereas PD-L2 expression was more common on lymphoma (63.2%) than stromal cells. PD-1 was positive in 20.5% of stroma, but undetectable on lymphoma cells. There was no association between baseline clinical characteristics and the expression PD-1/PD-Ls. The survival of patients with PD-Ls on tumor cells was poor. For PD-L1-positive versus negative cases, the 2-year event-free survival (EFS) was 42.2 versus 71.8% (p = 0.03) and 2-year overall survival (OS) was 45.4 versus 78.9% (p = 0.02), respectively. Comparing between patients with PD-L2-positive and PD-L2-negative lymphoma, the 2-year EFS was 37.1 versus 82.4% (p = 0.02) and 2-year OS was 45.2 versus 82.4% (p = 0.03), respectively. Neither PD-1 nor PD-Ls expression in the stroma predicted outcomes. In conclusion, PD-Ls were frequently expressed on ENKTL cells and associated with inferior outcomes. Therefore, PD-Ls are potential prognostic biomarkers and the roles of immune checkpoint blockade therapy in ENKTL deserve further investigation.

scholarly journals Increased Soluble CD226 in Sera of Patients with Cutaneous T-Cell Lymphoma Mediates Cytotoxic Activity against Tumor Cells via CD155

2017 ◽  
Vol 137 (8) ◽  
pp. 1766-1773 ◽  
Author(s):  
Naomi Takahashi ◽  
Makoto Sugaya ◽  
Hiraku Suga ◽  
Tomonori Oka ◽  
Makiko Kawaguchi ◽  
...  
Keyword(s):  
T Cell ◽  
Cytotoxic Activity ◽  
Tumor Cells ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma

Overcoming cell death resistance in cutaneous T cell lymphoma (CTCL) by combined Bcl-2 and NFκB inhibition

2018 ◽  
Vol 101 ◽  
pp. S29
Author(s):  
Tabea Schlör ◽  
Karin Müller-Decker ◽  
Anne Schröder ◽  
Karsten Gülow ◽  
Sergij Goerdt ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma

Interleukin-7 and interleukin-15 regulate the expression of thebcl-2 and c-myb genes in cutaneous T-cell lymphoma cells

Blood ◽  
2001 ◽  
Vol 98 (9) ◽  
pp. 2778-2783 ◽  
Author(s):  
Jian-Zhong Qin ◽  
Chun-Lei Zhang ◽  
Jivko Kamarashev ◽  
Reinhard Dummer ◽  
Günter Burg ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Cell Lymphoma ◽  
Skin Lesions ◽  
Test System ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Interleukin 7 ◽  
Survival Gene ◽  
Myb Genes

Abstract Interleukin-7 (IL-7) and IL-15 have been recently identified as growth factors for cutaneous T-cell lymphoma (CTCL) cells, and they protect these cells from cell death. Using the CTCL cell line SeAx as a test system now shows that IL-7 and IL-15 are indeed necessary to maintain high levels of bcl-2. The up-regulation of bcl-2 was paralleled by increased DNA-binding activities of the transcription factors STAT2, STAT5, STAT6, and c-Myb to bcl-2gene promoter–enhancer elements. Because STAT5 and c-Myb positively regulate bcl-2, IL-7 and IL-15 may mediate some of their effects on cell death survival gene expression through these 2 factors. Constitutive activities of the 3 STAT factors and c-Myb were found in the IL-7– and IL-15–independent CTCL cell lines HUT78 and MyLa 2059. The c-Myb protein was also present in CTCL cells of the skin lesions of all investigated patients. These results indicate that IL-7 and IL-15 may increase bcl-2 expression in CTCL cells by the activation of c-myb and STAT factors.

Differential Expression of the Homeobox Gene MIXL1 in Non Hodgkin (NHL) and Hodgkin Lymphomas (HL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3014-3014
Author(s):  
Elias Drakos ◽  
George Z. Rassidakis ◽  
Wei Guo ◽  
L. Jeffrey Medeiros ◽  
Lalitha Nagarajan
Keyword(s):  
T Cell ◽  
Protein Expression ◽  
B Cell ◽  
Tumor Cells ◽  
Cell Lymphoma ◽  
Lymphoblastic Leukemia ◽  
T Cell Lymphoma ◽  
High Grade ◽  
Intermediate Grade ◽  
Aberrant Expression

Abstract The gene MIXL1 (Mix1 homeobox-like) encodes a paired class homeobox transcription factor involved in early hematopoietic specification during embryogenesis. Previous studies have shown that MIXL1 gene is expressed in hematopoietic cells during adult life (Guo et al. Blood100;1;89–96, 2002). Furthermore 5′ MIXL1 sequences are a target of retroviral insertion in murine T-cell lymphoma (http:RTCGD.ncifcrf.gov), suggesting a selection advantage for aberrant expression of this gene. However, the status of MIXL1 expression in human lymphomas has not been examined. Using a highly specific antibody, we assessed for MIXL1 protein expression in 14 lymphoma cell lines (9 B-cell and 5 T-cell) by immunobloting. MIXL1 was detected predominantly in nuclear extracts of lysates of all cell lines tested, although at a variable level. We also assessed for MIXL1 protein expression in 126 B-cell and 21 T-cell NHLs of various types, as well as 14 Hodgkin lymphomas using immunohistochemical methods. The results of the immunohistochemical studies are summarized in table 1. Once again, MIXL1 immunoreactivity was primarily nuclear in the tumor cells. Based on distribution data (histogram), a 50% cutoff was selected for high versus low MIXL1 expression. Among B-cell tumors, high expression levels of MIXL1 protein were more frequently detected in high-grade NHL and HL compared with low/intermediate grade NHL (p<0.0001, chi-square test). As a continuous variable, the percentage of MIXL1-positive tumor cells was also significantly higher in high-grade B-cell NHL and HL compared with low/intermediate grade NHL (p<0.0001, Kruskal Wallis test). All Hodgkin lymphomas expressed high levels of MIXL1 with 60% to 100% of neoplastic cells being positive for MIXL1. Most T-cell NHLs also expressed high levels of MIXL1. In contrast, most low/intermediate-grade B-cell NHL and multiple myelomas expressed low levels of MIXL1. Frequent overexpression of MIXL1 gene product in most high-grade B-cell NHLs, HL and T-cell NHLs suggests that aberrant expression of MIXL1 may play a role in proliferation, block of differentiation or both. Table 1. HL (n=14) B-NHL (n =126) T-NHL (n =21) N (%) Low/intermediate grade N (%) N (%) Classical HL 12/12(100%) Chronic lymphocytic leukemia /small lymphocytic lymphoma 0/8 (0% T-precursor lymphoblastic leukemia/lymphoma 2/2 (0%) Nodular lymphocyte predominance HL 2/2 (100%) MALT-lymphoma 0/8 (0%) Mycosis fungoides/Sezary syndrome 2/2 (0%) Follicular lymphoma 9/24 (38%) Extranodal NK/T-cell lymphoma, nasal type 3/3 (100%) Mantle cell lymphoma 5/34 (15%) Peripheral T-cell lymphoma, unspecified 6/9 (66% High grade Anaplastic large cell lymphoma 5/5 (100%) B-precursor lymphoblastic leukemia/lymphoma 1/3 (33%) Burkitt lymphoma/leukemia 2/2 (100%) Diffuse large B-cell lymphoma 30/31 (97%) Plasma cell myeloma/plasmacytoma 0/16 (0%)

Bortezomib Induces Caspase-9-Mediated Apoptosis through Activation of the BH3-Only Proteins Noxa, Bik and Puma In Both ALK-Positive and ALK-Negative Anaplastic Large Cell Lymphoma Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2847-2847
Author(s):  
Saskia AGM Cillessen ◽  
Nathalie J Hijmering ◽  
Laura M Moesbergen ◽  
Gert J. Ossenkoppele ◽  
Joost J Oudejans ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Caspase 9 ◽  
Lymphoma Cells ◽  
Induction Of Apoptosis ◽  
Large Cell Lymphoma ◽  
Alk Positive

Abstract Abstract 2847 Anaplastic large cell lymphoma (ALCL) is a CD30 positive T-cell lymphoma that can be divided into a systemic and a primary cutaneous type. Systemic ALCL can be further divided into an anaplastic lymphoma kinase (ALK) expressing type and an ALK-negative type. Despite intensive treatment regimens, the disease will be fatal in 20–30% of the systemic ALK-positive and 50–70% of the systemic ALK-negative ALCL patients. A recent study in primary ALCL samples has demonstrated an increased expression of a fraction of NF-κB target genes, suggesting upregulation of NF-κB activity in ALCL tumor cells. NF-κB activity can be inhibited by the proteasome inhibitor bortezomib resulting in induction of apoptosis. In this study, we therefore investigated if bortezomib can induce apoptosis of cultured lymphoma cells of three systemic ALK-positive and three ALK-negative ALCL patients and seven ALCL cell lines and we examined the mechanisms by which bortezomib induced cytotoxicity in these ALCL cells. Treatment with bortezomib resulted in induction of apoptosis in all ALK-positive and ALK-negative ALCL patient samples and ALCL cell lines tested, when we compared the percentage cell death with the non-neoplastic CD4- and CD8-positive PBMC and tonsil T-cells from healthy donors. The lethal dose (LD50) varied between 54nM and more than 100nM after 24 hours and varied between 21nM and 52nM after 48 hours of exposure. ALK-negative ALCL cases were more sensitive to bortezomib and showed significant lower LD50 values than ALK-positive ALCL cells. We show that bortezomib-induced cell death in ALK-positive and ALK-negative ALCL is dependent on caspase-9 and/or caspase-8 mediated apoptosis and that bortezomib induces depolarization of the mitochondrial membrane. mRNA-expression and protein analysis revealed clearly upregulation of the BH3-only proteins Noxa, Bik and Puma, resulting in Bak and Bax release from the anti-apoptotic proteins Mcl-1 and Bcl-2. We also demonstrated that ALCL cells relatively resistant to bortezomib were characterized by high expression of Bcl-2A1, suggesting the possibility of pre-defining patients most likely to benefit from bortezomib therapy. Our preclinical data support the therapeutic application of bortezomib as potential drug in the treatment of ALCL, especially ALK-negative ALCL patients to improve their prognosis. Disclosures: No relevant conflicts of interest to declare.

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